20.500.12556/RUL-133422 Psoralen derivatives as inhibitors of mycobacterium tuberculosis proteasome Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the Mycobacterium tuberculosis proteasome in low micromolar concentrations. The best inhibitors, i.e., 8, 11, 13 and 15, exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. N-(cyanomethyl)acetamide 8 (K$_i$ = 5.6 µM) and carboxaldehyde-based derivative 15 (K$_i$ = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters 11 and 13 irreversibly inhibited the enzyme with K$_i$ values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, PR-957, is a noncompetitive irreversible inhibitor of the mycobacterial proteasome (K$_i$ = 5.2 ± 1.9 µM, k$_{inact}$/K$_i$ = 96 ± 41 M$^{−1}$·s$^{−1}$). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis. protein degradation proteasome Mycobacterium tuberculosis psoralens nonpeptidic proteasome inhibitors sinteza beljakovin zaviralci Mycobacterium tuberculosis imunoproteasom farmacevtska kemija beljakovine true false true Angleški jezik Slovenski jezik Članek v reviji 2021-11-26 12:11:24 2021-11-26 12:11:27 2022-09-13 03:50:43 0000-00-00 00:00:00 2020 0 0 14 str. iss. 6, art. 1305 Vol. 25 2020 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 547.96.057:615.4 1420-3049 10.3390/molecules25061305 4894321 RAZ_Rozman_Kaja_2020.pdf RAZ_Rozman_Kaja_2020.pdf 1 A0CF9586CFB79249DCD04C788F7D6B3E 5e533e01c0a4386b3a1ae8ca4a5bfe775b241f7428bccebcfe2d9387b651ebf8 cbae4edf-4ea9-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=151478 https://www.mdpi.com/1420-3049/25/6/1305 0 84100902-4ea9-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=151477 Fakulteta za farmacijo 0 0 0